In drug therapy for cancer, chemotherapeutics are frequently employed. Most such chemotherapeutics exhibit strong side effects in addition to anti-cancer effect. When adverse side effects are developed, in some cases administration of the cancer chemotherapeutic is inevitably restricted. In such a case, only insufficient effect of the drug may be obtained, or no effect at all may be obtained. In particular, in therapy for myeloma tumor, which is known as a malignant tumor producing very poor prognosis, such drugs as melphalan, cyclophosphamide, and prednisolone are used in clinical settings. However, thus far, satisfactory therapeutic effect has not been obtained.
Myeloma tumors are formed through tumorigenesis of antibody-producing cells, and include fusion products; i.e., hybridomas, of myeloma cells and other types of cells. Typical examples of myeloma tumors include malignant tumors such as multiple myeloma and solitary plasmocytoma; and benign pathologies including immunoglobulin abnormalities, such as M-proteinemia, hypergammaglobulinemia, and Castleman's syndrome.
Among various myeloma tumors, multiple myeloma represents a malignant, uncontrolled proliferation of plasma cells derived from a single clone. In most cases of this disease, patients develop significant osteoclastic bone-resorbing lesion accompanied by intractable acute pain and risk of easy osteoclastic bone loss. Meanwhile, histopathological research of bone slices has revealed significant activation of osteoclastic cells at bone-resorbing lesions neighboring myeloma cells. From this finding, it has been considered that, in multiple myeloma, osteoclastic bone loss is caused not only by infiltration (or multiplication) of myeloma cells but also by activation of osteoclastic cells which occurs due to the osteoclast activating factor (OAF) produced by myeloma cells (N. Engl. J. Med. 1974; 29: 1041-6) (Hematol. Oncol. Clin. North Am. 1992; 6: 285-95, Br. J. Haematol. 1981; 47: 21-30).
In recent years, several cytokines, such as IL-1β (Blood 1989; 74: 380-7), lymphotoxin (TNFβ) (N. Engl. J. Med. 1987; 317: 526-32, Nature 1986; 319: 516-8), and IL-6 (J. Clin. Invest. 1989; 84: 2008-11, J. Bone Min. Res. 1991; 9: 1143-6), have been found to exhibit OAF activity. Also, in view that most myeloma tumors exhibit cytokine-dependent growth (e.g., dependent on IL-6), a substance capable of inhibiting or regulating such cytokine-dependent growth in vitro or in vivo is considered to have anti-cancer activity against myeloma tumors.
Osteopontin is a secretory phosphorylated glycoprotein, and was initially identified as a substance forming the extracellular matrix of bone. Osteopontin is expressed in a diversity of cells such as osteoclastic cells, macrophages, activated T cells, smooth muscle cells, and epithelial cells, and in some tissues such as bones, kidneys, placenta, smooth muscles, and sectretory epithelium. Osteopontin has an RGD sequence (i.e., Arg-Gly-Asp sequence), and binds through αvβ1, β3, or β5 integrins in a variety of cells, to thereby induce cell adhesion, chemotaxis, and signal transmission. Osteopontin is considered to participate in normal tissue repairing processes in relation to bone resorption, angiogenesis, wound healing, and tissue injury, and also in some diseases such as restenosis, atherosclerosis, renal disorders, and tumors.
However, as described above, the myeloma tumor is quite a special tumor which only rarely responds to popular anti-cancer drugs. Therefore, components which would be effective have remained beyond expectation.
An object of the present invention is to provide preventives or remedies for myeloma tumors and osteoclastic bone loss associating therewith. Another object of the invention is to provide a screening method for candidate preventive or therapeutic drugs. A further object of the invention is to provide a method of diagnosing myeloma tumors.